Clinical Trials Register

Summary
EudraCT Number:	2014-001305-41
Sponsor's Protocol Code Number:	MicroVasc-DIVA
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-06-24
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2014-001305-41

A.3

Full title of the trial

MICROVASCULAR AND ANTIINFLAMMATORY EFFECTS OF RIVAROXABAN
COMPARED TO LOW DOSE ASPIRIN IN TYPE 2 DIABETIC PATIENTS WITH
VERY HIGH CARDIOVASCULAR RISK AND SUBCLINICAL INFLAMMATION

Mikrovaskuläre und anti-inflammatorische Effekte von Rivaroxaban im Vergleich zu niedrig-dosiertem Aspirin bei Typ-2 Diabetes Patienten mit sehr hohem kardiovaskulären Risiko und subklinischer Inflammation

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

MICROVASCULAR AND ANTIINFLAMMATORY EFFECTS OF RIVAROXABAN COMPARED TO ASPIRIN IN TYPE 2 DIABETIC PATIENTS WITH CARDIOVASCULAR RISK AND SUBCLINICAL INFLAMMATION

A.3.2

Name or abbreviated title of the trial where available

MicroVasc-DIVA

A.4.1

Sponsor's protocol code number

MicroVasc-DIVA

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GWT-TUD GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bayer Vital GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GWT-TUD GmbH
B.5.2	Functional name of contact point	Medical Consulting
B.5.3	Address:
B.5.3.1	Street Address	Blasewitzer Str.43
B.5.3.2	Town/ city	Dresden
B.5.3.3	Post code	01307
B.5.3.4	Country	Germany
B.5.4	Telephone number	004935125933188
B.5.5	Fax number	35125933111
B.5.6	E-mail	katja.jersemann@gwtonline.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	XARELTO
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	XARELTO
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RIVAROXABAN
D.3.9.1	CAS number	366789-02-8
D.3.9.4	EV Substance Code	SUB29263
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	ASS-ratiopharm® 100 mg TAH
D.2.1.1.2	Name of the Marketing Authorisation holder	Ratiopharm GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ASS-ratiopharm® 100 mg TAH
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACETYLSALICYLIC ACID
D.3.9.1	CAS number	50-78-2
D.3.9.3	Other descriptive name	ACETYLSALICYLIC ACID
D.3.9.4	EV Substance Code	SUB12730MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with type 2 diabetes and stable cardiovascular disease (CVD) and low grade inflammation

E.1.1.1

Medical condition in easily understood language

Patients with type 2 diabetes and stable cardiovascular disease (CVD) and inflammation

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Difference of change of forearm blood flow with venous occlusion plethysmography at baseline and after forearm ischemia after 20 weeks treatment between rivaroxoban and aspirin therapy.
Additionally the difference of arterial stiffness after the end of the extension study (week 52) between rivaroxoban and aspirin therapy will be evaluated.

Änderung des maximalen postischämischen Unterarmblutflusses während der reaktiven Hyperämie nach 5 min Ischämie des Unterarms (FBF max. ml/100ml) bei EOT.
Zusätzlich soll die Gefäßsteifigkeit am Ende der erweiterten Therapieperiode nach 52 Wochen zwischen beiden Behandlungsgruppen (Rivaroxaban und Aspirin) evaluiert werden.

E.2.2

Secondary objectives of the trial

 change of peripheral skin microcirculatory function after 20 and 52 weeks of treatment
 LDF baseline
 LDF after ischemia (endothelial function)
 arterial stiffness measured after 20 weeks of treatment
 laboratory markers for endothelial function
 VCAM, ICAM, E-Selectin, ADMA, Nitrotyrosin, P-Selectin, CD40-L
 Microalbuminuria, eGFR
 composite of biomarkers of inflammation
 hsCRP, PAI-1, MCP-1, MMP-9, fibrinogen, leucocytes, MPO, IL-6, IL-8
 side effects: major bleeding according to ISTH, thromboembolic events
 metabolic marker: HbA1c, lipids: triglycerides, LDL-C, HDL-C
 coagulation marker: von Willebrand-Factor, Fibrinogen, Prothrombinfragment, D-Dimer, Protein C, Protein S, TAT, Quick, aPTT
 cardiovascular marker: NT-proBNP, hs-Tnl, GDF-15, MR-ANP

Additional secondary objective for extension period:
 Difference of change of forearm blood flow with venous occlusion plethysmography at baseline and after forearm ischemia after 52 weeks treatment

 Änderung der Fläche unter der Kurve postischämischer FBF über 10 Zyklen der intermittierende venöse Stauung (im Vergleich zum Ausgangswert)
 maximale postischämische Hautdurchblutung während der reaktiven Hyperämie nach 5 min Ischämie des Unterarms bei EOT mit LDF
 Änderung der postischämischen Hautdurchblutung mit LDF
 Pulswellengeschwindigkeit bei EOT im Vergleich zum Ausgangswert
 Laborparameter bei EOT

Zusätzliche sekundäre Objectives der Extension Periode:
 Unterschied der Änderung des Fore Arm Bloodflow mit venösem Verschluss zu Untersuchungsbeginn und nach 52 Wochen Therapie

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

 type 2 diabetes duration between 2 and 20 years
 two or more components of metabolic syndrome:
- HDL cholesterol < 1.0 mmol/L (in males) or < 1.3 mmol/L (in females)
- Elevated triglycerides (> 1,7 mmol/L)
- Elevated blood pressure (>130 mmHg systolic and/or >85 mmHg diastolic or antihypertensive treatment)
- Elevated waist circumference (>102 cm in males , > 85 cm in females)
 or at least one of the following
- carotid ultrasound showing an IMT > 1 mm and plaque of carotid artery or
- left ventricular hypertrophy or
- increased UACR in the absence of other renal diseases than diabetic nephropathy
 increased hsCRP (> 2 mg/l but < 10 mg/l) at or within 6 months prior
to screening and/or increased PAI 1 (> 15 ng/ml) at or within 6
months prior to screening (the historical hsCrP or PAI 1 value can
be used only if the patient was in stable conditions regarding the
concomitant diseases and statin therapy since the time point of
measurement)
 stable treatment with statines (if tolerated)
 age 40 – 75 years

E.4

Principal exclusion criteria

Principal exclusion criteria:
 major CV event with need for oral anticoagulation or platelet inhibitor therapy or acute coronary syndrome < 12 month before study entry
 sustained uncontrolled hypertension: systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg
 hypersensitivity to the active substance or to any of the excipients
 active clinically significant bleeding
 lesion or condition, if considered to be a significant risk for major
bleeding
 concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or a transient ischaemic attack (TIA)
 hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C
 chronic renal failure with eGFR < 15 ml/min (MDRD formula)
 Pregnant or breast-feeding woman and woman without adequate method of contraception.

E.5 End points

E.5.1

Primary end point(s)

Primary variable
 change of maximal postischemic forearm blood flow during reactive hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml) at EOT

Additional primary variable for extension period:
 pulse wave velocity at EOT after 52 weeks

E.5.1.1

Timepoint(s) of evaluation of this end point

20 weeks and 52 weeks

E.5.2

Secondary end point(s)

 change of the area under the postischemic FBF curve over 10 cycles of intermittent venous congestion (compared to baseline) after 20 weeks and EOT Extension
 change of maximal postischemic forearm blood flow during reactive hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml) at EOT after 52 weeks
 maximal postischemic skin blood flow (arbitrary units) during reactive hyperaemia after 5 min of forearm ischemia at 20 weeks and EOT Extension using LDF
 change of postischemic skin blood flow (compared to baseline) using LDF
 Pulse wave velocity at EOT 20 weeks compared to baseline
 laboratory parameter (see above) at 20 weeks and EOT Extension

Additional secondary variable for extension period:
 change of maximal postischemic forearm blood flow during reactive hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml) at EOT after 52 weeks (EOT Extension)

E.5.2.1

Timepoint(s) of evaluation of this end point

20 weeks and 52 weeks

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS or if not LVLS premature termination of the trial will be considered if:
 if risk-benefit ratio becomes unacceptable owing to,
 safety findings from this study
 results of any interim analysis (not planned yet), results of parallel clinical studies provided by the manufacturer, if the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol compliance) does not suggest a proper completion of the trial within a reasonable time frame.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

188

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

188

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

Yes

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

188

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

protocol section describing post trial treatment plans:
4.3 End of the clinical trial:
After conclusion, patient will receive standard medical care as usual for this kind of disease. As for this study the primary objective will be analyzed after LPLV, the end of the study as a whole will be the date when the clean database is available.
5.12 Post-study therapy:
After ending of the clinical trial, patients will receive further standard medical care as usual for this kind of disease.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-11-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-12-12

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